miRNA interplay: mechanisms and consequences in cancer

Abstract

Canonically, microRNAs (miRNAs) control mRNA expression. However, studies have shown that miRNAs are also capable of targeting non-coding RNAs, including long non-coding RNAs and miRNAs. The latter, termed a miRNA:miRNA interaction, is a form of self-regulation. In this Review, we discuss the three main modes of miRNA:miRNA regulation: direct, indirect and global interactions, and their implications in cancer biology. We also discuss the cell-type-specific nature of miRNA:miRNA interactions, current experimental approaches and bioinformatic techniques, and how these strategies are not sufficient for the identification of novel miRNA:miRNA interactions. The self-regulation of miRNAs and their impact on gene regulation has yet to be fully understood. Investigating this hidden world of miRNA self-regulation will assist in discovering novel regulatory mechanisms associated with disease pathways.

Keywords: RNA regulation; miRNA regulation; miRNA:miRNA interaction.

Fig. 1.

Direct miRNA:miRNA interactions. These occur either between two mature miRNAs in the cytoplasm or a mature and a primary miRNA hairpin in the nucleus. These nuclear interactions typically prevent the binding of Microprocessor and thus block the maturation of the primary miRNA, reducing its levels and preventing the silencing of its target mRNA. The cytoplasmic interaction between two mature miRNAs is sequence specific and brings together two miRNA-bound RNA-induced silencing complexes (miRISCs). However, the functional consequences of this interaction on miRISC activity are not fully understood.

Fig. 2.

Indirect miRNA:miRNA interactions. These interactions occur through miRNA-directed suppression of the miRNA biogenesis pathway components or transcriptional regulators. The suppression of the biogenesis components has consequences on the production of specific miRNAs, rather than the expected negative effect on overall miRNA production. Targeted transcriptional regulators may include transcription factors, DNA methyltransferases and repressors.

Fig. 3.

Global miRNA:miRNA interactions are due to the culmination of the reactions within the cell that control miRNA expression. These consider all direct and indirect changes in miRNA and mRNA expression in response to a perturbation in miRNA expression. Full comprehension of the complexity of miRNA:miRNA interactions in a cellular system involves the integration of several mechanisms, and the consideration of resultant secondary changes in miRNA and mRNA.